Natural and recombinant proteins and polypeptides have been used as medicines. The products after purification and separation can be used to treat specific diseases by parenteral routes. When administered parenterally, however, proteins may have immunogenecity, or be relatively insoluble in water, or have short pharmacological half-lives. How to raise and keep a highly effective serum concentration in vivo is of significant importance.
In addition to proteins, clinically there is necessity to modify other constituents of natural medicine such as flavonoids, terpenoids, anthraquinones, steroids and alkaloids to prolong their physiological half-lives, enhance their stability and the possibility to reach the target site, raise their solubility in water, change administration routes and improve bioavailability.
Recently PEG has been widely used to conjugate proteins, peptides or other therapeutic agents, in order to prolong their physiological half-lives and lower their immunogenicity and toxicity. Clinically, PEG and its derivatives have been widely used as carriers in the manufacture of pharmaceutical preparations of commercial drugs. The methods for conjugating PEG to drug molecules has made much progress in the last 10 years and had been applied to many officially approved drugs. For example, PEG-intron®, a conjugate of PEG to α-interferon, exhibits longer circulation half-life and better therapeutic effect. The conjugate of PEG to paclitaxel reduces the toxicity and increases the bioactivity. The metabolism of PEG is well known, and PEG is accepted as a safe drug modifier.
One process called PEGylation is often applied when conjugating PEG to drugs. Namely, one or two of the terminal groups of the PEG are activated to form a proper functional group, which is reactive to at least one functional group of the drugs, and can form a stable bond with it.
Many PEG derivatives have been reported. Linear PEG propionic acid, butanoic acid and their NHS esters have been reported in U.S. Pat. No. 5,672,662. Recently a U-shape branched PEG is reported in U.S. Pat. No. 564,357. In these PEG derivatives, two linear PEGs link to one molecule or structure through two identical functional groups, such as two amino groups or two carboxyl groups. In one example of the patent, the branched PEG is derived from linear PEG and lysine, which is a kind of amino acid having two amino groups.